Phosphatidylcholine transfer protein inhibitors

ABSTRACT

This invention relates to compounds of Formulas I, II, and III, and their use as inhibitors of phosphatidylcholine transfer protein (PC-TP). The invention further relates to pharmaceutical compositions and methods of treatment of disorders related to the inhibition of PC-TP using the compounds of Formulas I, II, and III. Such disorders include obesity and disorders associated with obesity.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant Nos. R01DK48873 and R01 DK56626 awarded by the National Institutes of Health.The Government has certain rights in the invention.

This application is a §371 National Stage Application of InternationalApplication PCT/US2010/045752, filed Aug. 17, 2010, which claims thebenefit of priority of U.S. Provisional Appl. No. 61/234,545, filed Aug.17, 2009, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to inhibitors of phosphatidylcholinetransfer protein (PC-TP), pharmaceutical compositions thereof, andmethods of treatment of disorders related thereto.

BACKGROUND

Obesity has become an epidemic in the U.S. and other developedcountries. As many as one-third of all Americans over 30 years of ageare obese, based on the body mass index (BMI) criteria, and as many asone in three adults in the United States are attempting to loose weight.Each year, 30 billion dollars is spent on the treatment of obesity. Yet,despite this, less is known about the causes of obesity than is knownabout the causes of most other medical conditions. Accordingly, there isa need to develop new compounds for treatment of obesity and disordersassociated with obesity. This invention addresses this need and others.

SUMMARY

The present invention provides, inter alia, compounds of Formulas I, II,or III:

and their pharmaceutically acceptable salts, as well as pharmaceuticalcompositions comprising the compounds described herein.

The present invention further provides methods of treating obesity,disorders associated with obesity and disorders treatable with PC-TPinhibitors or reducing the risk of obesity using the compounds describedherein, and their pharmaceutically acceptable salts. Also provided aremethods of reducing a subject's risk of developing a disorder associatedwith obesity, disorders associated with obesity and disorders treatablewith PC-TP inhibitors using the compounds described herein.

The present invention also provides compounds as described herein foruse in treatment of obesity, disorders associated with obesity, anddisorders treatable by PC-TP inhibitors or reducing the risk of obesity.The present invention further provides the use of the compoundsdescribed herein for the manufacture of a medicament for use intreatment of obesity, disorders associated with obesity, and disorderstreatable by PC-TP inhibitors, or reducing the risk of obesity. In someembodiments, the disorders treatable by PC-TP inhibitor include, but arenot limited to, type 2 diabetes, non-alcoholic fatty liver disease,asthma, hypertension, hyperlipidemia, coronary artery disease,arthritis, gallstones, osteoarthritis, atherosclerosis, sleep apnea,depression, cancer, and gastroesophagael reflux disease.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts activation of the insulin-signaling pathway in humanheptacycles for Compounds 4 and 16.

FIG. 2 depicts the results of a surface plasmon resonance study ofCompound 8 binding to PC-TP.

FIG. 3 depicts results from a displacement assay of PC-TP using aPyrene-labeled PC for Compound 4.

DETAILED DESCRIPTION

The present invention provides, inter alia:

(a) a compound of Formula I or II:

wherein:

X is N or CR⁸;

Y is N or CR⁹;

Z is N or CR¹⁰;

W is O or S;

R′, R″, and R′″ are each independently selected from H and C₁₋₄ alkyl;wherein said C₁₋₄ alkyl is optionally substituted withdi-C₁₋₄-alkylamino;

R¹, R², R³, R⁴, and R⁵ are each independently selected from H, halogen,cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(a′) groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(a″) groups;

or R¹ and R², together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(a″) groups;

or R² and R³, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(a″) groups;

or R³ and R⁴, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(a″) groups;

R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H, halogen,cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(b′) groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(b″) groups;

or R⁶ and R⁸, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(b″) groups;

or R⁶ and R¹⁰, together with the carbon atoms to which they areattached, form an phenyl or C₁₋₆ heteroaryl ring, which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b″) groups;

or R⁷ and R⁹, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(b″) groups;

or R⁷ and R¹⁰, together with the carbon atoms to which they areattached, form an phenyl or C₁₋₆ heteroaryl ring, which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b″) groups;

each R¹¹ is independently selected from halogen, cyano, nitro, hydroxyl,carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl;

each R^(a′) and R^(b′) is independently selected from halogen, cyano,nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄alkylamino, and di-C₁₋₄-alkylamino;

each R^(a″) and R^(b″) is independently selected from halogen, cyano,nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino; and

n is an integer selected from 0, 1, 2, 3, and 4;

(b) a compound of Formula III:

wherein:

each R^(a) is independently selected from halogen, cyano, nitro,hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl;

or any two adjacent R^(a) groups, together with the atoms to which theyare attached, form a phenyl or C₁₋₆ heteroaryl group; each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(a′)groups;

R^(s), R^(t), R^(o), R^(p), and R^(q) are each independently selectedfrom H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl,di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, and C₁₋₆ alkylsulfonyl; wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally substituted by1, 2, or 3 independently selected R^(o′) groups;

R^(u), R^(w), R^(x), R^(y), and R^(z) are each independently selectedfrom H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl,di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, and C₁₋₆ alkylsulfonyl;

or R^(y) and R^(z), together with the carbon atoms to which they areattached, form a phenyl ring or C₁₋₆ heteroaryl ring, each of which isoptionally substituted by 1, 2, or 3 R^(g) groups;

or R^(u) and R^(y), together with the carbon atoms to which they areattached, form a phenyl ring or C₁₋₆ heteroaryl ring, each of which isoptionally substituted by 1, 2, or 3 R^(g) groups;

each R^(a′) is independently selected from halogen, cyano, nitro,hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl;

each R^(g) is independently selected from halogen, cyano, nitro,hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl;

each R^(o′) is independently selected from halogen, cyano, nitro,hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄alkylamino, and di-C₁₋₄-alkylamino; and

n is an integer selected from 0, 1, 2, 3, and 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a compound asdescribed above wherein R, R″, and R′″ are each independently selectedfrom H and C₁₋₄ alkyl.

In some embodiments, R¹, R², R³, R⁴, and R⁵ are each independentlyselected from H, halogen, cyano, hydroxyl, carboxyl, carbamyl, amino,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(a′) groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(a″) groups.

In some embodiments, the compound is not selected from any of thecompounds in Appendix I, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is not selected from compounds 2 and 3of Table 1, or a pharmaceutically acceptable salt thereof. In someembodiments, the compound is not selected from any of the compounds inAppendix I and compounds 2 and 3 of Table 1, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the compound is a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

X is N or CR⁸;

Y is N or CR⁹;

Z is N or CR¹⁰;

W is O;

R′, R″, and R′″ are each independently selected from H and C₁₋₄ alkyl;wherein said C₁₋₄ alkyl is optionally substituted by di-C₁₋₆-alkylamino;

R¹, R², R³, R⁴, and R⁵ are each independently selected from H, halogen,cyano, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(a′) groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(a″) groups;

or R¹ and R², together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(a″) groups;

or R² and R³, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(a″) groups;

or R³ and R⁴, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(a″) groups;

R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H, halogen,cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(b′) groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl,and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(b″) groups;

or R⁶ and R⁸, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(b″) groups;

or R⁶ and R¹⁰, together with the carbon atoms to which they areattached, form an phenyl or C₁₋₆ heteroaryl ring, which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b″) groups;

or R⁷ and R⁹, together with the carbon atoms to which they are attached,form an phenyl or C₁₋₆ heteroaryl ring, which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(b″) groups;

or R⁷ and R¹⁰, together with the carbon atoms to which they areattached, form an phenyl or C₁₋₆ heteroaryl ring, which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(b″) groups;

each R¹¹ is independently selected from halogen, cyano, nitro, hydroxyl,carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl;

each R^(a′) and R^(b′) is independently selected from halogen, cyano,nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄alkylamino, and di-C₁₋₄-alkylamino;

each R^(a″) and R^(b″) is independently selected from halogen, cyano,nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino; and

n is an integer selected from 0, 1, 2, 3, and 4;

provided that:

(1) when the compound has Formula I, W is O, Z is CH, n is 0, R¹, R²,R⁴, R⁵, R⁶ and R⁷ are each H, and either X is N and Y is CH, or X is CHand Y is N, then R³ is other than chloro; and

(2) when the compound has Formula I, W is O, X is N, Y is N, and Z isCR¹⁰, then the following provisos apply:

-   -   (a) when R⁶ and R⁷ are each methyl or each H, R¹⁰ is H, and R¹,        R², R⁴, and R⁵ are H, then R³ is not methoxy or chloro; and    -   (b) when R⁶ and R⁷ are each methyl or each H and R¹⁰ is H, then        at least one of R¹, R², R³, R⁴, and R⁵ is other than H.

In some embodiments, W is S. In some embodiments, W is O.

In some embodiments, n is 0.

In some embodiments, each R¹¹ is independently selected from halogen,C₁₋₄ alkyl and C₁₋₄ haloalkyl. In some embodiments, each R¹¹ isindependently halogen.

In some embodiments, R′, R″, and R′″ are each independently selectedfrom H and methyl. In some embodiments, R′, R″, and R′″ are eachindependently selected from H and methyl, provided at least two of R′,R″, and R′″ are H. In some embodiments, R′, R″, and R′″ are eachindependently selected from H and methyl, provided at least one of R′,R″, and R′″ is H. In some embodiments, R′, R″, and R′″ are each H.

In some embodiments, R¹, R², R³, R⁴, and R⁵ are each independentlyselected from H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl,amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl. In some embodiments, R¹, R², R³, R⁴, and R⁵ are eachindependently selected from H, halogen, cyano, nitro, and hydroxyl. Insome embodiments, R¹, R², R³, R⁴, and R⁵ are each independently selectedfrom H and halogen. In some embodiments, R¹ and R³ are eachindependently chloro.

In some embodiments, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independentlyselected from H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl,amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylthio, and C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl. In some embodiments, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are eachindependently selected from H, hydroxyl, amino, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,C₁₋₆ alkylamino, and di-C₁₋₆-alkylamino. In some embodiments, R⁶, R⁷,R⁸, R⁹, and R¹⁰ are each independently H and C₁₋₆ alkyl. In someembodiments, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently H andmethyl. In some embodiments, R⁶ and R⁷ are each independently methyl.

In some embodiments, R⁶ and R⁷ are each other than H. In someembodiments, either one or both of R⁶ or R⁷ is other H.

In some embodiments, X is N, Y is N, and Z is CH. In some embodiments, Xis N, Y is CH, and Z is CH. In some embodiments, X is N, Y is CH, and Zis N. In some embodiments, X is CH, Y is CH, and Z is CH.

In some embodiments, the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound is a compound of Formula II, or a pharmaceutically acceptablesalt thereof.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₃        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆        alkylsulfonyl;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylthio, and C₁₋₆ alkylsulfinyl, and C₁₋₆        alkylsulfonyl; and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₂        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, nitro, and hydroxyl;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from        hydroxyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, and        di-C₁₋₆-alkylamino; and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and        methyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H        and halogen;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently H and C₁₋₆ alkyl;        and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and        methyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H        and chloro;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently H and methyl; and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₃        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylcarbamyl,        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylcarbamyl,        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylthio, and C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;        provided that one or both of R⁶ and R⁷ are other than H; and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₂        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, nitro, and hydroxyl;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from        hydroxyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, and        di-C₁₋₆-alkylamino; provided that one or both of R⁶ and R⁷ are        other than H; and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and        methyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H        and halogen;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently H and C₁₋₆ alkyl;        provided that one or both of R⁶ and R⁷ are other than H; and    -   n is 0.

In some embodiments:

-   -   X is N, Y is N, and Z is CH; or    -   X is N, Y is CH, and Z is CH; or    -   X is N, Y is CH, and Z is N; or    -   X is CH, Y is CH, and Z is CH;    -   R′, R″, and R′″ are each independently selected from H and        methyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H        and chloro;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently H and methyl;        provided that one or both of R⁶ and R⁷ are other than H; and    -   n is 0.

In any of the preceding embodiments, the compound may be a compound ofFormula Ia:

or a pharmaceutically acceptable salt thereof.

In any of the preceding embodiments, the compound may be a compound ofFormula Ib:

or a pharmaceutically acceptable salt thereof. In some embodiments, W isS. In some embodiments, W is O.

In any of the preceding embodiments, the compound may be a compound ofFormula Ic:

or a pharmaceutically acceptable salt thereof. In some embodiments, W isS. In some embodiments, W is O.

In any of the preceding embodiments, the compound may be a compound ofFormula Id:

or a pharmaceutically acceptable salt thereof. In some embodiments, W isS. In some embodiments, W is O.

In any of the preceding embodiments, the compound may be a compound ofFormula Ie:

or a pharmaceutically acceptable salt thereof. In some embodiments, W isS. In some embodiments, W is O.

In any of the preceding embodiments, the compound may be a compound ofFormula If:

or a pharmaceutically acceptable salt thereof. In some embodiments, W isS. In some embodiments, W is O.

In some of the preceding embodiments, when the compound has Formula I, Wis O, Z is CH, n is 0, R¹, R², R⁴, R⁵, R⁶ and R⁷ are each H, and eitherX is N and Y is CH, or X is CH and Y is N, then R³ is other than chloro.

In some of the preceding embodiments, when the compound has Formula I, Wis O, Z is CH, n is 0, R¹, R², R⁴, R⁵, R⁶ and R⁷ are each H, and eitherX is N and Y is CH, or X is CH and Y is N, then R³ is other thanhalogen.

In some of the preceding embodiments, when the compound has Formula I, Wis O, Z is CH, n is 0, R⁶ and R⁷ are each H and either X is N and Y isCH, or X is CH and Y is N, then R¹, R², R³, R⁴, and R⁵ are other thanhalogen.

In some embodiments, the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

-   -   X is N and Y is CH; or    -   X is CH and Y is N;    -   Z is CH;    -   W is O;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₄        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl,        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆        alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(a′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(a″) groups;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylcarbamyl,        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇        heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆        heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, alkylcarbonylamino, C₁₋₆        alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R^(b′) groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇        heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆        heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(b″)        groups;    -   each R¹¹ is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl,        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆        alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   each R^(a′) and R^(b′) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino;    -   each R^(a″) and R^(b″) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and        di-C₁₋₄-alkylamino; and    -   n is an integer selected from 0, 1, 2, 3, and 4.

In some of the preceding embodiments, when W is S, X is CR⁸, Y is CR⁹,and Z is CR¹⁰, then the compound does not have Formula I.

In some of the preceding embodiments, when W is S, X is CR⁸, Y is CR⁹,and Z is CR¹⁰, then the compound does not have Formula I.

In some of the preceding embodiments, when the compound has Formula II,W is S, X is CR⁸, Y is CR⁹, and Z is CR¹⁰, then the following provisosapply:

(a) n is 0;

(b) if one of R¹ or R⁵ is chloro and four of R¹, R², R³, R⁴, and R⁵ areH, then at least one of R⁶ and R⁷ is other than trifluoromethyl;

(c) if one of R¹ or R⁵ is bromo and four of R¹, R², R³, R⁴, and R⁵ areH, then at least one of R⁸ or R⁹ is other than methoxy;

(d) if one of R² or R⁴ is nitro and four of R¹, R², R³, R⁴, and R⁵ areH, then at least one of R⁶ and R⁷ is other than chloro;

(e) if

is 2-bromo-5-methylphenyl, then

is not naphth-2-yl; and

(f) if R² and R⁴ are each methoxy and R¹, R³, and R⁵ are each H, then

is not 2-bromo-5-methylphenyl.

In some of the preceding embodiments, when the compound has Formula II,W is S, X is CR⁸, Y is CR⁹, and Z is CR¹⁰, then the following provisosapply:

(a) n is 0;

(b) if one of R¹ or R⁵ is halogen and four of R¹, R², R³, R⁴, and R⁵ areH, then at least one of R⁶ and R⁷ is other than C₁₋₄ haloalkyl;

(c) if one of R¹ or R⁵ is halogen and four of R¹, R², R³, R⁴, and R⁵ areH, then at least one of R⁸ or R⁹ is other than C₁₋₄ alkoxy;

(d) if one of R² or R⁴ is nitro and four of R¹, R², R³, R⁴, and R⁵ areH, then at least one of R⁶ and R⁷ is other than halogen;

(e) if

is 2-(halogen)-5-(C₁₋₄ alkyl)phenyl, then

is not a naphthalene ring; and

(f) if R² and R⁴ are each C₁₋₄ alkoxy and R¹, R³, and R⁵ are each H,then

is not 2-(halogen)-5-(C₁₋₄ alkyl)phenyl.

In some embodiments, the compound is a compound of Formula II, or apharmaceutically acceptable salt thereof, wherein:

-   -   W is S;    -   X is CR⁸, Y is CR⁹, and Z is CR¹⁰;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₄        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl,        C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, alkylcarbonylamino,        C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇        cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl,        C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl,        C₁₋₆ heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(a′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(a″) groups;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,        di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl,        C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇        heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆        heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino,        C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl,        C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆        alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4        independently selected R^(b′) groups; and wherein C₃₋₇        cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl,        C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl,        C₁₋₆ heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R^(b″) groups;    -   each R¹¹ is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   each R^(a′) and R^(b′) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino;    -   each R^(a″) and R^(b″) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and        di-C₁₋₄-alkylamino; and    -   n is 0.

In some of the preceding embodiments, X is not CR⁸, Y is not CR⁹, and Zis not CR¹⁰.

In some of the preceding embodiments, when the compound has Formula I, Wis O, X is N, Y is N, and Z is CR¹⁰, then the following provisos apply:

-   -   (a) when R⁶ and R⁷ are each methyl or each H, R¹⁰ is H, and R¹,        R², R⁴, and R⁵ are H, then R³ is not methoxy or chloro;    -   (b) when R⁶ and R⁷ are each methyl or each H and R¹⁰ is H, then        at least one of R¹, R², R³, R⁴, and R⁵ is other than H; and    -   (c) when R¹⁰ is bromo, R⁶ and R⁷ each H, and at least four of        R¹, R², R³, R⁴, and R⁵ are H, then R¹ or R⁵ is other than nitro.

In some of the preceding embodiments, when the compound has Formula I, Wis O, X is N, Y is N, and Z is CR¹⁰, where R¹⁰ is H or halogen, then thefollowing provisos apply:

-   -   (a) when R⁶ and R⁷ are each methyl or each H, R¹⁰ is H, and R¹,        R², R⁴, and R⁵ are H, then R³ is not C₁₋₃ alkoxy or halogen;    -   (b) when R⁶ and R⁷ are each methyl or each H and R¹⁰ is H, then        at least one of R¹, R², R³, R⁴, and R⁵ is other than H; and    -   (c) when R¹⁰ is bromo, R⁶ and R⁷ each H, and at least four of        R¹, R², R³, R⁴, and R⁵ are H, then R¹ or R⁵ is other than nitro.

In some of the preceding embodiments, when the compound has Formula I, Wis O, X is N, Y is N, and Z is CR¹⁰, where R¹⁰ is H or halogen, then R¹,R², R³, R⁴, and R⁵ are not selected from halogen, nitro, or C₁₋₃ alkoxy.

In some embodiments, the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

-   -   W is O;    -   X is N, Y is N, and Z is CR¹⁰;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₄        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,        di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl,        C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇        heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆        heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,        di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl,        C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(a′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(a″) groups;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(b′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄ alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(b″) groups;    -   each R¹¹ is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   each R^(a′) and R^(b′) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino;    -   each R^(a″) and R^(b″) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and        di-C₁₋₄-alkylamino; and    -   n is an integer selected from 0, 1, 2, 3, and 4;        provided that when R⁶ and R⁷ are each methyl or each H; and R¹⁰        is H; then at least one of R¹, R², R³, R⁴, and R⁵ is other than        H.

In some of the preceding embodiments, when the compound has Formula I, Wis S, X is N, Y is CH, and Z is N, then the following provisos apply:

(a) R⁷ is not methoxy; and

(b) the compound is not selected from4-chloro-N-(4-(N-(6-methylpyrimidin-4-yl)sulfamoyl(phenylcarbamothioyl)benzamideorN-(4-(N-(2,6-dimethylpyrimidin-4-yl)sulfamoyl(phenylcarbamothioyl)-3,4-difluorobenzamide;or a pharmaceutically acceptable salt thereof.

In some of the preceding embodiments, when the compound has Formula I, Wis S, X is N, Y is CH, and Z is N, then the following provisos apply:

(a) R⁷ is not methoxy;

(b) when R⁷ is methyl, R⁶ is H, and R¹, R², R⁴, and R⁵ are H, then R³ isother than chloro; and

(c) when R⁶ and R⁷ are each methyl and R³ is fluoro, then at least oneof R² or R⁴ is other than fluoro.

In some of the preceding embodiments, when the compound has Formula I, Wis S, X is N, Y is CH, and Z is N, then the following provisos apply:

(a) R⁷ is not C₁₋₄ alkoxy; and

(b) when R⁶ or R⁷ are methyl, then R³ is other than halogen.

In some embodiments, when the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

-   -   W is S;    -   X is N, Y is CR⁹, and Z is N;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₄        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(a′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(a″) groups;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇        cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl, C₂₋₇        heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆        heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl,        C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆        alkylsulfonyl are each optionally substituted by 1, 2, 3, or 4        independently selected R^(b′) groups; and wherein C₃₋₇        cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl, C₂₋₁₄ heterocycloalkyl,        C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl, phenyl, phenyl-C₁₋₄-alkyl,        C₁₋₆ heteroaryl, and C₁₋₆ heteroaryl-C₁₋₄-alkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R^(b″) groups;    -   each R¹¹ is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl,        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆        alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   each R^(a′) and R^(b′) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino;    -   each R^(a″) and R^(b″) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and        di-C₁₋₄-alkylamino; and    -   n is an integer selected from 0, 1, 2, 3, and 4;        provided that:

(a) when Y is CH, R⁷ is methyl, R⁶ is H, and R¹, R², R⁴, and R⁵ are H,then R³ is other than halogen; and

(b) when Y is CH, R⁶ and R⁷ are each methyl and R³ is fluoro, then atleast one of R² or R⁴ is other than halogen.

In some of the preceding embodiments, when the compound has Formula I, Wis S, X is N, Y is N, and Z is CH, then the following provisos apply:

(a) when R⁶ and R⁷ are each methyl and at least two of R¹, R², R³, R⁴,and R⁵ are H, then the remaining R¹, R², R³, R⁴, and R⁵ are not selectedfrom nitro, C₁₋₄ alkyl, C₁₋₆ alkoxy, methoxycarbonyl, and phenyl;wherein said C₁₋₆ alkoxy is optionally substituted by a C₁₋₄ alkoxy;

(b) when R⁶ and R⁷ are each methyl or each H, then at least one of R²,R³, R⁴, and R⁵ is other than H;

(c) when R⁶ and R⁷ are each H and at least four of R¹, R², R³, R⁴, andR⁵ are other than H, then the remaining R¹, R², R³, R⁴, or R⁵ are notselected from halogen;

(d) when R⁶ and R⁷ are each methyl, the moiety

is 2,4-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R¹ us chloro, then R³ is other than chloro;

(e) when R⁶ and R⁷ are each methyl, the moiety

is 2,5-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R¹ is chloro, then R⁴ is other than bromo, iodo,or chloro;

(f) when R⁶ and R⁷ are each methyl, the moiety

is 3,4-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R² is chloro or fluoro, then R³ is other thanchloro or fluoro;

(g) when R⁶ and R⁷ are each methyl and at least four of R¹, R², R³, R⁴and R⁵ are H, then the remaining R¹, R², R³, R⁴ or R⁵ is not halogen;

(h) when one of R⁶ and R⁷ is methyl and the other of R⁶ and R⁷ is H, andat least four of R¹, R², R³, R⁴, and R⁵ are H, then R³ is other thanmethyl.

(i) when R⁶ and R⁷ are each methyl, then the moiety

is not a naphthalene ring, which is optionally substituted by methoxy.

In some of the preceding embodiments, when the compound has Formula I, Wis S, X is N, Y is N, and Z is CH, then the following provisos apply:

(a) when R⁶ and R⁷ are each methyl, then R¹, R², R³, R⁴, and R⁵ are notselected from nitro, C₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, andphenyl; wherein said C₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(a′) groups;

(b) when R⁶ and R⁷ are each methyl or each H, then at least one of R¹,R², R³, R⁴, and R⁵ is other than H, methyl, or ethyl.

(c) when R⁶ and R⁷ are each H, then R¹, R², R³, R⁴, and R⁵ are notselected from halogen;

(d) when R⁶ and R⁷ are each methyl, the moiety

is 2,4-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R¹ is halogen, then R³ is other than halogen;

(e) when R⁶ and R⁷ are each methyl, the moiety

is 2,5-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R¹ is halogen, then R⁴ is other than halogen;

(f) when R⁶ and R⁷ are each methyl, the moiety

is 3,4-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R² is halogen, then R³ is other than halogen;

(g) when R⁶ and R⁷ are each methyl and at least four of R¹, R², R³, R⁴and R⁵ are H, then the remaining R¹, R², R³, R⁴ or R⁵ is not halogen;

(h) when one of R⁶ and R⁷ is methyl and the other of R⁶ and R⁷ is H, andat least four of R¹, R², R³, R⁴, and R⁵ are H, then R³ is other thanC₁₋₃ alkyl; and

(i) when R⁶ and R⁷ are each methyl, then the moiety

is not a naphthalene ring, which is optionally substituted by C₁₋₃alkoxy.

In some of the preceding embodiments, when the compound has Formula I, Wis S, X is N, Y is N, and Z is CH, then the following provisos apply:

(a) when R⁶ and R⁷ are each methyl, then R¹, R², R³, R⁴, and R⁵ are notselected from halogen, nitro, C₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, and phenyl; wherein said C₁₋₄ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(a′) groups;

(b) when R⁶ and R⁷ are each methyl or each H, then at least one of R¹,R², R³, R⁴, and R⁵ is other than H, methyl or ethyl;

(c) when R⁶ and R⁷ are each H, then R¹, R², R³, R⁴, and R⁵ are notselected from halogen;

(d) when one of R⁶ and R⁷ is methyl and the other of R⁶ and R⁷ is H, andat least four of R¹, R², R³, R⁴, and R⁵ are H, then R³ is other thanC₁₋₄ alkyl; and

(e) when R⁶ and R⁷ are each methyl, then the moiety

is does not form an optionally substituted fused aryl or heteroarylring.

In some embodiments, when the compound is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

-   -   W is S;    -   X is N, Y is N, and Z is CR¹⁰;    -   R′, R″, and R′″ are each independently selected from H and C₁₋₄        alkyl;    -   R¹, R², R³, R⁴, and R⁵ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(a′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(a″) groups;    -   R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H,        halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₆-alkyl,        phenyl, phenyl-C₁₋₆-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₆-alkyl; wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl are each optionally        substituted by 1, 2, 3, or 4 independently selected R^(b′)        groups; and wherein C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄-alkyl,        C₂₋₁₄ heterocycloalkyl, C₂₋₇ heterocycloalkyl-C₁₋₄-alkyl,        phenyl, phenyl-C₁₋₄-alkyl, C₁₋₆ heteroaryl, and C₁₋₆        heteroaryl-C₁₋₄-alkyl are each optionally substituted by 1, 2,        3, or 4 independently selected R^(b″) groups;    -   each R¹¹ is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   each R^(a′) and R^(b′) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino;    -   each R^(a″) and R^(b″) is independently selected from halogen,        cyano, nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylamino, and        di-C₁₋₄-alkylamino; and    -   n is an integer selected from 0, 1, 2, 3, and 4;        provided that:

(a) when Z is CH, R⁶ and R⁷ are each methyl and at least two of R¹, R²,R³, R⁴, and R⁵ are H, then the remaining R¹, R², R³, R⁴, and R⁵ are notselected from nitro, C₁₋₄ alkyl, C₁₋₆ alkoxy, methoxycarbonyl, andphenyl; wherein said C₁₋₆ alkoxy is optionally substituted by a C₁₋₄alkoxy;

(b) when Z is CH, R⁶ and R⁷ are each methyl or each H, then at least oneof R¹, R², R³, R⁴, and R⁵ is other than H;

(c) when Z is CH, R⁶ and R⁷ are each H and at least four of R¹, R², R³,R⁴, and R⁵ are other than H, then the remaining R¹, R², R³, R⁴, or R⁵are not selected from halogen;

(d) when Z is CH, R⁶ and R⁷ are each methyl, the moiety

is 2,4-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R¹ is chloro, then R³ is other than chloro;

(e) when Z is CH, R⁶ and R⁷ are each methyl, the moiety

is 2,5-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R¹ is chloro, then R⁴ is other than bromo, iodo,or chloro;

(f) when Z is CH, R⁶ and R⁷ are each methyl, the moiety

is 3,4-disubstituted with groups other than H, the remaining positionsare unsubstituted, and R² is chloro or fluoro, then R³ is other thanchloro or fluoro;

(g) when Z is CH, R⁶ and R⁷ are each methyl and at least four of R¹, R²,R³, R⁴ and R⁵ are H, then the remaining R¹, R², R³, R⁴ or R⁵ is nothalogen; and

(h) when Z is CH, one of R⁶ and R⁷ is methyl and the other of R⁶ and R⁷is H, and at least four of R¹, R², R³, R⁴, and R⁵ are H, then R³ isother than methyl.

Each of the preceding provisos can be presented separately or in anysuitable combination.

The present invention further provides a compound of Formula III:

or a pharmaceutically acceptable salt thereof; wherein:

-   -   each R^(a) is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   or any two adjacent R^(a) groups, together with the atoms to        which they are attached, form a phenyl or C₁₋₆ heteroaryl group;        each of which is optionally substituted by 1, 2, 3, or 4        independently selected R^(a′) groups;    -   R^(s), R^(t), R^(o), R^(p), and R^(q) are each independently        selected from H, halogen, cyano, nitro, hydroxyl, carboxyl,        carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,        di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl,        C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl; wherein the C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,        C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆        alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆        alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆        alkylsulfonyl are each optionally substituted by 1, 2, or 3        independently selected R^(o′) groups;    -   R^(u), R^(w), R^(x), R^(y), and R^(z) are each independently        selected from H, halogen, cyano, nitro, hydroxyl, carboxyl,        carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,        di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl,        C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   or R^(y) and R^(z), together with the carbon atoms to which they        are attached, form a phenyl ring or C₁₋₆ heteroaryl ring, each        of which is optionally substituted by 1, 2, or 3 R^(g) groups;    -   or R^(u) and R^(y), together with the carbon atoms to which they        are attached, form a phenyl ring or C₁₋₆ heteroaryl ring, each        of which is optionally substituted by 1, 2, or 3 R^(g) groups;

each R^(a′) is independently selected from halogen, cyano, nitro,hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl;

-   -   each R^(g) is independently selected from halogen, cyano, nitro,        hydroxyl, carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆        alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆        alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆        alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio,        C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylsulfonyl;    -   each R^(o′) is independently selected from halogen, cyano,        nitro, hydroxyl, carboxyl, amino, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,        C₁₋₄ alkylamino, and di-C₁₋₄-alkylamino; and    -   n is an integer selected from 0, 1, 2, 3, and 4.

In some embodiments, the compound is not selected from compounds 18, 19,and 28 of Table 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, n is 0.

In some embodiments, each R^(a) is independently selected from halogen,cyano, nitro, hydroxyl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, andC₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di-C₁₋₃-alkylamino. In someembodiments, each R^(a) is independently selected from halogen, cyano,nitro, hydroxyl, C₁₋₃ alkyl, C₁₋₃ haloalkyl, and C₁₋₃ alkoxy.

In some embodiments, R^(s), R^(t), R^(o), R^(p), and R^(q) are eachindependently selected from H, halogen, cyano, nitro, hydroxyl,carboxyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, and C₁₋₆ alkylsulfonyl.In some embodiments, R^(s), R^(t), R^(o), R^(p), and R^(q) are eachindependently selected from H, halogen, cyano, nitro, hydroxyl,carboxyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, and C₁₋₆ alkylsulfonyl.In some embodiments, R^(s), R^(t), R^(o), R^(p), and R^(q) are eachindependently selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy. In some embodiments, R^(s), R^(t), R^(o),R^(p), and R^(q) are each independently selected from H, halogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, and C₁₋₆ alkoxy. In some embodiments, R^(s),R^(t), R^(o), R^(p), and R^(q) are each independently selected from H,chloro, methyl, trifluoromethyl, and methoxy.

In some embodiments, R^(u), R^(w), R^(x), R^(y), and R^(z) are eachindependently selected from H, halogen, cyano, nitro, hydroxyl,carboxyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, and C₁₋₆ alkylsulfonyl;or R^(y) and R^(z), together with the carbon atoms to which they areattached, form a phenyl ring; or R^(u) and R^(y), together with thecarbon atoms to which they are attached, form a phenyl ring. In someembodiments, R^(u), R^(w), R^(x), R^(y), and R^(z) are eachindependently selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, and C₁₋₆ haloalkoxy; or R^(y) and R^(z), together with thecarbon atoms to which they are attached, form a phenyl ring; or R^(u)and R^(y), together with the carbon atoms to which they are attached,form a phenyl ring. In some embodiments, R^(u), R^(w), R^(x), R^(y), andR^(z) are each independently selected from H, halogen, and C₁₋₆ alkoxy;or R^(y) and R^(z), together with the carbon atoms to which they areattached, form a phenyl ring; or R^(u) and R^(y), together with thecarbon atoms to which they are attached, form a phenyl ring. In someembodiments, R^(u), R^(w), R^(x), R^(y), and R^(z) are eachindependently selected from H, chloro, and methoxy; or R^(y) and R^(z),together with the carbon atoms to which they are attached, form a phenylring; or R^(u) and R^(y) together with the carbon atoms to which theyare attached, form a phenyl ring.

In some embodiments:

-   -   R^(s), R^(t), R^(o), R^(p), and R^(q) are each independently        selected from H, halogen, cyano, nitro, hydroxyl, carboxyl,        amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, and C₁₋₆ alkylsulfonyl; and    -   R^(u), R^(w), R^(x), R^(y), and R^(z) are each independently        selected from H, halogen, cyano, nitro, hydroxyl, carboxyl,        amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,        C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, and C₁₋₆ alkylsulfonyl;    -   or R^(y) and R^(z), together with the carbon atoms to which they        are attached, form a phenyl ring;    -   or R^(u) and R^(y), together with the carbon atoms to which they        are attached, form a phenyl ring.

In some embodiments:

-   -   R^(s), R^(t), R^(o), R^(p), and R^(q) are each independently        selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy;    -   R^(u), R^(w), R^(x), R^(y), and R^(z) are each independently        selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy;    -   or R^(y) and R^(z), together with the carbon atoms to which they        are attached, form a phenyl ring; and    -   or R^(u) and R^(y), together with the carbon atoms to which they        are attached, form a phenyl ring.

In some embodiments:

-   -   R^(s), R^(t), R^(o), R^(p), and R^(q) are each independently        selected from H, halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and C₁₋₆        alkoxy; and    -   R^(u), R^(w), R^(x), R^(y), and R^(z) are each independently        selected from H, halogen, and C₁₋₆ alkoxy;    -   or R^(y) and R^(z), together with the carbon atoms to which they        are attached, form a phenyl ring;    -   or R^(u) and R^(y), together with the carbon atoms to which they        are attached, form a phenyl ring.

In some embodiments:

-   -   R^(s), R^(t), R^(o), R^(p), and R^(q) are each independently        selected from H, chloro, methyl, trifluoromethyl, and methoxy;        and    -   R^(u), R^(w), R^(x), R^(y), and R^(z) are each independently        selected from H, chloro, and methoxy;    -   or R^(y) and R^(z), together with the carbon atoms to which they        are attached, form a phenyl ring;    -   or R^(u) and R^(y), together with the carbon atoms to which they        are attached, form a phenyl ring;

In any of the preceding embodiments, the compound may be a compound ofFormula IIIa

or a pharmaceutically acceptable salt thereof. In some embodiments, n is0.

In any of the preceding embodiments, the compound may be a compound ofFormula IIIb:

or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; andm is an integer selected from 1, 2, 3, and 4.

At various places in the present specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the compounds include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclosemethyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further appreciated that certain features, which are, for clarity,described in the context of separate embodiments, can also be providedin combination in a single embodiment. Conversely, various featureswhich are, for brevity, described in the context of a single embodiment,can also be provided separately or in any suitable subcombination.

For compounds in which a variable appears more than once, each variablecan be a different moiety independently selected from the group definingthe variable. For example, where a structure is described having two Rgroups that are simultaneously present on the same compound, the two Rgroups can represent different moieties independently selected from thegroup defined for R. In another example, when an optionally multiplesubstituent is designated in the form:

then it is understood that substituent R can occur p number of times onthe ring, and R can be a different moiety at each occurrence. It isunderstood that each R group may replace any hydrogen atom attached to aring atom, including one or both of the (CH₂)_(n) hydrogen atoms.Further, in the above example, should the variable Q be defined toinclude hydrogens, such as when Q is the to be CH₂, NH, etc., anyfloating substituent such as R in the above example, can replace ahydrogen of the Q variable as well as a hydrogen in any othernon-variable component of the ring. Unless otherwise indicated, shouldfloating substituent R appear on a fused ring system, the substituentmay replace a hydrogen atom at any ring atom in the fused ring system.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compoundsdescribed herein that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds describedherein may be isolated as a mixture of isomers or as separated isomericforms. Where a compound capable of stereoisomerism or geometricisomerism is designated in its structure or name without reference tospecific R/S or cis/trans configurations, it is intended that all suchisomers are contemplated.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds described herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds described herein further include hydrates and solvates, aswell as anhydrous and non-solvated forms. Compounds described herein canalso include all isotopes of atoms occurring in the intermediates orfinal compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. For example, isotopes of hydrogeninclude tritium and deuterium.

The compounds can also include salt forms of the compounds describedherein. Examples of salts (or salt forms) include, but are not limitedto, mineral or organic acid salts of basic residues such as amines,alkali or organic salts of acidic residues such as carboxylic acids, andthe like. Generally, the salt forms can be prepared by reacting the freebase or acid with stoichiometric amounts or with an excess of thedesired salt-forming inorganic or organic acid or base in a suitablesolvent or various combinations of solvents.

The compounds also include pharmaceutically acceptable salts of thecompounds disclosed herein. As used herein, the term “pharmaceuticallyacceptable salt” refers to a salt formed by the addition of apharmaceutically acceptable acid or base to a compound disclosed herein.As used herein, the phrase “pharmaceutically acceptable” refers to asubstance that is acceptable for use in pharmaceutical applications froma toxicological perspective and does not adversely interact with theactive ingredient. Pharmaceutically acceptable salts, including mono-and bi-salts, include, but are not limited to, those derived fromorganic and inorganic acids such as, but not limited to, acetic, lactic,citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic,ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly knownacceptable acids. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in their entireties.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substitutent. It isunderstood that substitution at a given atom is limited by valency.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbon atoms. Insome embodiments, the alkyl group contains 1 to 6, or 1 to 4 carbonatoms. Examples of alkyl moieties include, but are not limited to,chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,tert-butyl, isobutyl, sec-butyl, 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, n-octyl, and the like.

As used herein, “C_(n-m) alkenyl”, employed alone or in combination withother terms, refers to an alkyl group having one or more doublecarbon-carbon bonds and n to m carbon atoms. In some embodiments, thealkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(n-m) alkynyl”, employed alone or in combination withother terms, refers to an alkyl group having one or more triplecarbon-carbon bonds, which may also optionally have one or more doublecarbon-carbon bonds, and having n to m carbon atoms. In someembodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to an group of formula —O-alkyl,having n to m carbon atoms. Example alkoxy groups include methoxy,ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and thelike.

As used herein, the term “amino”, employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “C_(n-m) alkylamino”, employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di-C_(n-m) alkylamino”, employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each alkyl group independently has n to m carbon atoms. In someembodiments, each alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl”, employed alone or incombination with other terms, refers to a group of formula —C(O)O-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl”, employed alone or incombination with other terms, refers to a group of formula —C(O)-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylthio”, employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfinyl”, employed alone or incombination with other terms, refers to a group of formula —S(O)-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl”, employed alone or incombination with other terms, refers to a group of formula —S(O)₂-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl”, employed alone or incombination with other terms, refers to a group of formula—C(O)NH-alkyl, wherein the alkyl group has n to m carbon atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di-C_(n-m) alkylcarbamyl”, employed alone orin combination with other terms, refers to a group of formula—C(O)N(alkyl)₂, wherein each alkyl group independently has n to m carbonatoms. In some embodiments, each alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamine”, employed alone orin combination with other terms, refers to a group of formula—NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di-C_(n-m) alkylcarbonylamine”, employed aloneor in combination with other terms, refers to a group of formula—N(alkyl)C(O)-alkyl, wherein each alkyl group independently has n to mcarbon atoms. In some embodiments, each alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “carbamyl”, employed alone or in combinationwith other terms, refers to a —C(O)NH₂ group.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “carboxy”, employed alone or in combinationwith other terms, refers to a group of formula —C(O)OH.

As used herein, the term “cyano”, employed alone or in combination withother terms, refers to a group of formula —CN.

As used herein, the terms “halo” and “halogen”, employed alone or incombination with other terms, refer to fluoro, chloro, bromo, and iodo.In some embodiments, halogen is fluoro.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from n tom carbon atoms and one halogen atom to 2x+1 halogen atoms which may bethe same or different, where “x” is the number of carbon atoms in thealkyl group. In some embodiments, the halogen atoms are fluoro atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Anexample of a haloalkyl group is —CF₃.

As used herein, “C_(n-m) haloalkoxy”, employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl, wherein thehaloalkyl group has n to m carbon atoms. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms. An example haloalkoxy group is—OCF₃.

As used herein, the term “C_(n-m) cycloalkyl”, employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety, which may optionally contain one or more alkenyleneor alkynylene groups as part of the ring structure, and which has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ringsystems. The term “cycloalkyl” also includes bridgehead cycloalkylgroups and spirocycloalkyl groups. As used herein, “bridgeheadcycloalkyl groups” refers to non-aromatic cyclic hydrocarbon moietiescontaining at least one bridgehead carbon, such as admantan-1-yl. Asused herein, “spirocycloalkyl groups” refers to non-aromatic hydrocarbonmoieties containing at least two rings fused at a single carbon atom,such as spiro[2.5]octane and the like. In some embodiments, thecycloalkyl group has 3 to 14 ring members, 3 to 10 ring members, or 3 to7 ring members. In some embodiments, the cycloalkyl group is monocyclicor bicyclic. In some embodiments, the cycloalkyl group is monocyclic. Insome embodiments, the cycloalkyl group is a C₃₋₇ monocyclic cycloalkylgroup. One or more ring-forming carbon atoms of a cycloalkyl group canbe oxidized to form carbonyl linkages. Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In someembodiments, the cycloalkyl group is admanatan-1-yl.

As used herein, the term “C_(n-m) cycloalkylene” refers to a divalentcycloalkyl group having n to m carbon atoms.

As used herein, the term “C_(n-m) cycloalkyl-C_(o-p) alkyl”, employedalone or in combination with other terms, refers to a group of formula-alkylene-cycloalkyl, wherein the cycloalkyl portion has n to m carbonatoms and the alkylene portion has o to p carbon atoms. In someembodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1carbon atom(s). In some embodiments, the alkylene portion is methylene.In some embodiments, the cycloalkyl portion has 3 to 14 ring members, 3to 10 ring members, or 3 to 7 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl portion is monocyclic. In some embodiments, the cycloalkylportion is a C₃₋₇ monocyclic cycloalkyl group.

As used herein, the term “x-membered cycloalkyl ring” refers to amonocyclic cycloalkyl ring having x ring members.

As used herein, the term “C_(n-m) heterocycloalkyl”, “C_(n-m)heterocycloalkyl ring”, or “C_(n-m) heterocycloalkyl group”, employedalone or in combination with other terms, refers to non-aromatic ring orring system, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur andoxygen, and which has n to m ring member carbon atoms. Heterocycloalkylgroups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused,bridged, or spiro rings) ring systems. In some embodiments, theheterocycloalkyl group is a monocyclic or bicyclic group having 1, 2, 3,or 4 hetereoatoms independently selected from nitrogen, sulfur andoxygen. Also included in the definition of heterocycloalkyl are moietiesthat have one or more aromatic rings (e.g., heteroaryl or aryl rings)fused (e.g., having a bond in common with) to the non-aromatic ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups andspiroheterocycloalkyl groups. As used herein, “bridgeheadheterocycloalkyl group” refers to a heterocycloalkyl moiety containingat least one bridgehead atom, such as azaadmantan-1-yl and the like. Asused herein, “spiroheterocycloalkyl group” refers to a heterocycloalkylmoiety containing at least two rings fused at a single atom, such as[1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like. In someembodiments, the heterocycloalkyl group has 3 to 20 ring-forming atoms,3 to 10 ring-forming atoms, or about 3 to 8 ring forming atoms. Thecarbon atoms or hetereoatoms in the ring(s) of the heterocycloalkylgroup can be oxidized to form a carbonyl, or sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group.

As used herein, the term “x-membered heterocycloalkyl ring” refers to amonocyclic heterocycloalkyl ring having x ring members.

As used herein, the term “C_(n-m) heterocycloalkyl-C_(a) alkyl”,employed alone or in combination with other terms, refers to a group offormula -alkylene-heterocycloalkyl, wherein the heterocycloalkyl portionhas n to m carbon atoms and the alkylene portion has o to p carbonatoms. In some embodiments, the alkylene portion has 1 to 4, 1 to 3, 1to 2, or 1 carbon atom(s). In some embodiments, the alkylene portion ismethylene. In some embodiments, the heterocycloalkyl portion has 3 to 14ring members, 3 to 10 ring members, or 3 to 7 ring members. In someembodiments, the heterocycloalkyl group is monocyclic or bicyclic. Insome embodiments, the heterocycloalkyl portion is monocyclic. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group.

As used herein, the term “C_(n-m) aryl”, employed alone or incombination with other terms, refers to a monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon moiety havingn to m ring member carbon atoms, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. Alsoincluded in the definition of aryl are moieties that have one or morecycloalkyl or heterocycloalkyl rings fused (i.e., having a bond incommon with) to the aryl ring. In some embodiments, aryl groups havefrom 6 to 14 carbon atoms, about 6 to 10 carbon atoms, or about 6carbons atoms. In some embodiments, the aryl group is a monocyclic orbicyclic group.

As used herein, the term “C_(n-m) aryl-C_(o-p)-alkyl”, employed alone orin combination with other terms, refers to a group of formula-alkylene-aryl, wherein the aryl portion has n to m ring member carbonatoms and the alkylene portion has o to p carbon atoms. In someembodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1carbon atom(s). In some embodiments, the alkylene portion is methylene.In some embodiments, the aryl portion is phenyl. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the arylalkyl group is benzyl.

As used herein, the term “C_(n-m) heteroaryl”, “C_(n-m) heteroarylring”, or “C_(n-m) heteroaryl group”, employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members independently selected from nitrogen, sulfur andoxygen and having n to m ring member carbon atoms. Also included in thedefinition of heteroaryl are moieties that have one or more cycloalkylor heterocycloalkyl rings fused (i.e., having a bond in common with) tothe aryl ring. In some embodiments, the heteroaryl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 hetereoatoms independentlyselected from nitrogen, sulfur and oxygen. Example heteroaryl groupsinclude, but are not limited to, pyrrolyl, azolyl, oxazolyl, thiazolyl,imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolyl,benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl orthe like. The carbon atoms or hetereoatoms in the ring(s) of theheteroaryl group can be oxidized to form a carbonyl, or sulfonyl group(or other oxidized linkage) or a nitrogen atom can be quaternized,provided the aromatic nature of the ring is preserved for at least onering of the heteroaryl moiety. In some embodiments, the heteroaryl grouphas 5 to 10 carbon atoms.

As used herein, the term “x-membered heteroaryl ring” refers to amonocyclic heteroaryl ring having x ring members.

As used herein, the term “C_(n-m) heteroaryl-C_(o-p)-alkyl”, employedalone or in combination with other terms, refers to a group of formula-alkylene-heteroaryl, wherein the heteroaryl portion has n to m ringmember carbon atoms and the alkylene portion has to p carbon atoms. Insome embodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1carbon atom(s). In some embodiments, the alkylene portion is methylene.In some embodiments, the heteroaryl portion is a monocyclic or bicyclicgroup having 1, 2, 3, or 4 hetereoatoms independently selected fromnitrogen, sulfur and oxygen. In some embodiments, the heteroaryl portionhas 5 to 10 carbon atoms.

As used herein, the term “oxo” refers to a group of formula “═O”.

The term “protecting group” includes, but are not limited to, theprotecting groups described in Greene, et al., Protective Groups inOrganic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporatedherein by reference in its entirety.

Unless otherwise indicated herein, the point of attachment of asubstituent is generally in the last portion of the name (e.g.,arylalkyl is attached through the alkylene portion of the group).

Methods, Pharmaceutical Formulations and Dosage Forms

Certain compounds described herein are PC-TP inhibitors. PC-TP (alsoreferred to as StarD2) is a soluble phosphatidylcholine-binding proteinand a member of the steroidogenic acute regulatory protein-relatedtransfer (START) domain superfamily (Ponting, C. P., and Aravind, L.1999. START: a lipid-binding domain in StAR, HD-ZIP and signallingproteins. Trends Biochem. Sci. 24:130-132; Roderick, S. L., Chan, W. W.,Agate, D. S., Olsen, L. R., Vetting, M. W., Rajashankar, K. R., andCohen, D. E. 2002. Structure of human phosphatidylcholine transferprotein in complex with its ligand. Nature Struct. Biol. 9:507-511).Expression of PC-TP is accentuated in highly oxidative tissues in themouse, including liver, brown fat, heart, and muscle (Kanno, K., Wu, M.K., Scapa, E. F., Roderick, S. L., and Cohen, D. E. 2007. Structure andfunction of phosphatidylcholine transfer protein (PC-TP)/StarD2.Biochim. Biophys. Acta 1771:654-662). Among the phenotypes of mice withhomozygous disruption of the Pctp gene (Pctp^(−/−)) are increasedhepatic insulin sensitivity and redistribution of body fat, both ofwhich appear to be attributable to preferential use of fatty acids overglucose as energy substrates (Scapa, E. F., Pocai, A., Wu, M. K.,Gutierrez-Juarez, R., Glenz, L., Kanno, K., Li, H., Biddinger, S.,Jelicks, L. A., Rossetti, L., and Cohen, D. E. 2008. Regulation ofenergy substrate utilization and hepatic insulin sensitivity byphosphatidylcholine transfer protein/StarD2. FASEB J 22:2579-259). Micethat lack expression of both PC-TP and apolipoprotein E (ApoE) arerelatively resistant to atherosclerosis when compared withApoE-deficient mice (Wang, W. J., Baez, J. M., Maurer, R., Dansky, H.M., and Cohen, D. E. 2006. Homozygous disruption of Pctp modulatesatherosclerosis in apolipoprotein E deficient mice. J. Lipid Res.47:2400-2407). Moreover, an unbiased genetic screen of awell-characterized human population revealed that a coding regionpolymorphism in the Pctp gene is associated with larger, lessatherogenic low-density lipoprotein (LDL) particles (Dolley, G.,Berthier, M. T., Lamarche, B., Despres, J. P., Bouchard, C., Perusse,L., and Vohl, M. C. 2007. Influences of the phosphatidylcholine transferprotein gene variants on the LDL peak particle size. Atherosclerosis195:297-302). PC-TP was identified, and has been characterizedextensively based on its in vitro activity (Wirtz, K. W. 1991.Phospholipid Transfer Proteins. Annu. Rev. Biochem. 60:73-99), which isto bind and catalyze the intermembrane exchange of phosphatidylcholines,but no other lipid.

Recently, yeast two-hybrid screening (Kanno, K., Wu, M. K., Agate, D.A., Fanelli, B. K., Wagle, N., Scapa, E. F., Ukomadu, C., and Cohen, D.E. 2007. Interacting proteins dictate function of the minimal STARTdomain phosphatidylcholine transfer protein/StarD2. J. Biol. Chem.282:30728-30736) has led to the suggestion that the function(s) of PC-TPin vivo may be dictated at least in part by interacting proteins. Onesuch protein is thioesterase superfamily member 2 (Them2), which ismitochondrial associated (Mootha, V. K., Bunkenborg, J., Olsen, J. V.,Hjerrild, M., Wisniewski, J. R., Stahl, E., Bolouri, M. S., Ray, H. N.,Sihag, S., Kamal, M., Patterson, N., Lander, E. S., and Mann, M. 2003.Integrated analysis of protein composition, tissue diversity, and generegulation in mouse mitochondria. Cell 115:629-640; Wei, J., Kang, H. W.and Cohen, D. E. 2009. Thioesterase superfamily member 2(Them2)/acyl-CoA thioesterase 13 (Acot13): A homotetrameric hotdog foldthioesterase with selectivity for long chain fatty acyl-CoAs. Biochem.J. 421, 311-322) and exhibits acyl-coenzyme A (CoA) thioesteraseactivity (Kanno, Wei supra). This suggests the possibility that PC-TPmay participate in mitochondrial fatty acid metabolism (de Brouwer, A.P., Westerman, J., Kleinnijenhuis, A., Bevers, L. E., Roelofsen, B., andWirtz, K. W. A. 2002. Clofibrate-induced relocation ofphosphatidylcholine transfer protein to mitochondria in endothelialcells. Exp. Cell Res. 274:100-111; Kanno, K., Wu, M. K., Scapa, E. F.,Roderick, S. L., and Cohen, D. E. 2007. Structure and function ofphosphatidylcholine transfer protein (PC-TP)/StarD2. Biochim. Biophys.Acta 1771:654-662). The observation that it also interacts withdevelopmentally expressed transcription factor Pax3 raises thepossibility that PC-TP could also regulate transcription in certain celltypes (Kanno supra).

It has been demonstrated that Pctp^(−/−) mice are protected againstdiet-induced diabetes and allergen-induced asthma (infra). This suggeststhat the compounds described herein could be effective in the treatmentof asthma. Finally, the Cohen laboratory has demonstrated that brown fatfunctions more efficiently in Pctp^(−/−) mice (Kang H, Ribich S, Kim BW, Hagen S J, Bianco A C, Cohen D E. “Mice lacking phosphatidylcholinetransfer protein/StarD2 exhibit increased adaptive thermogenesis andenlarged mitochondria in brown adipose tissue”, J Lipid Res 2009, inpress.). Three recently published studies (van Marken Lichtenbelt etal., 2009. N. Engl. J. Med. 360:1500-1508; Cypess et al., 2009. N. Engl.J. Med. 360:1509-1517; and Virtanen et al., 2009. N. Engl. J. Med.360:1518-1525) have shown that brown fat plays an important role inenergy utilization in adult humans (which was not previouslyappreciated) and may protect against obesity. Compounds that increasebrown fat efficiency there are likely to have utility as anti-obesityagents.

The methods described herein include methods for the treatment ofobesity, reducing the risk of obesity, treating disorders associatedwith obesity, and treating disorders treatable by a PC-TP inhibitor. Insome embodiments, the methods include treating or reducing the risk ofobesity in a patient or individual in need thereof. Generally, themethods include administering a therapeutically effective amount oftherapeutic compound as described herein, to a subject who is in needof, or who has been determined to be in need of, such treatment. Themethods can include a step of selecting a subject on the basis of thepresence of obesity or a symptom of a disorder associated with obesity.The methods include administering a therapeutically effective amount ofa compound of Formula I, II, or III, or any embodiment thereof, or apharmaceutically acceptable salt thereof, to the individual. In someembodiments, the disorders treatable by a PC-TP inhibitor include type 2diabetes, non-alcoholic fatty liver disease, asthma, hypertension,hyperlipidemia, coronary artery disease, arthritis, gallstones,osteoarthritis, atherosclerosis, sleep apnea, depression, cancer, andgastroesophagael reflux disease. Cancers in include esophageal squamous(Zhi, H., Zhang, J., Hu, G., Lu, J., Wang, X., Zhou, C., Wu, M. and Liu,Z. 2003. The deregulation of arachidonic acid metabolism-related genesin human esophageal squamous cell carcinoma. Int. J. Cancer 106,327-333) and cancers related to obesity (Brawer, R., Brisbon, N. andPlumb, J. 2009. Obesity and cancer. Prim. Care 36, 509-531).

The present invention also provides a compound of Formula I, II, or III,or any embodiment thereof, or a pharmaceutically acceptable saltthereof, for use in a method of treating obesity, disorders associatedwith obesity, and disorders treatable by PC-TP inhibitors, or reducingrisk of obesity, in an individual.

The present invention also provides use of a compound of Formula I, II,or III, or any embodiment thereof, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for use in treatment ofobesity, disorders associated with obesity, and disorders treatable by aPC-TP inhibitor, or reducing risk of obesity, in an individual.

The present invention also provides kits including one or more compoundsof Formula I, II, or III, or any embodiment thereof, or pharmaceuticallyacceptable salts thereof; and instructions, wherein the instructionsinclude a direction to administer a therapeutically effective amount ofthe compound or the salt to an individual in need of treatment ofobesity, disorders associated with obesity, and disorders treatable by aPC-TP inhibitor, or reducing risk of obesity in an individual.

The present invention further provides pharmaceutical compositionsincluding one or more compounds according to Formula I, II, or III, orany embodiment thereof, or pharmaceutically acceptable salts thereof,and a pharmaceutically acceptable carrier.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing (i.e., reducingthe risk of developing) a disease, condition or disorder in anindividual who may be predisposed to the disease, condition or disorderbut does not yet experience or display the pathology or symptomatologyof the disease; (2) inhibiting the disease; for example, inhibiting(e.g., slowing progression of) a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder; and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein “body mass index (BMI)” refers to a mathematical formulaused to assess relative body weight. BMI is generally used to defineoverweight and obesity. BMI may be calculated using the formula ‘weight(kg)/Height2 (m).’ BMI may be determined by a clinician or may beestimated by a subject using standard tables.

As used herein, “obesity” refers to a disorder in a subject, where thesubject's weight exceeds their ideal weight, according to standardtables by 20% or more, e.g., 25%, 30%, 40%, and 50% or more. Obesity mayalso mean an individual with a body mass index (BMI) of 30 or more,e.g., 30-35 and 35-40 or more. For example, a subject diagnosed withclass I obesity has a BMI range of 30-34.9. A subject with class IIobesity has a BMI range of 35.0-39.9. A subject with class III obesityhas a BMI greater than 40.

As used herein, “overweight” refers to a subject with a BMI range of25.0-29.9.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. For example, a therapeutic amount isone that achieves the desired therapeutic effect, e.g., weight loss,e.g., sufficient weight loss to reduce the subject's risk of developingan obesity-related disorder.

In some embodiments, a therapeutically effective amount ranges fromabout 0.001 to 30 mg/kg body weight, for example, about 0.01 to 25 mg/kgbody weight, about 0.1 to 20 mg/kg body weight, or about 1 to 10 mg/kg,2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.In some embodiments, the compound may be administered one or severaltimes per day or per week for between about 1 to 10 weeks, for example,between 2 to 8 weeks, between about 3 to 7 weeks, or about 4, 5, or 6weeks.

When employed as pharmaceuticals, the compounds described herein can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.Coated condoms, gloves and the like may also be useful.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds described hereinin combination with one or more pharmaceutically acceptable carriers(excipients). In making the compositions, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds described herein may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds described herein can beprepared by processes known in the art, for example see InternationalPatent Application No. WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions can be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), or about 100 to about500 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, about 0.1 to about 1000 mg of a compound describedherein.

The tablets or pills can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permit the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compounds and compositions describedherein can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds described herein can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds described herein can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

Preparation of the Compounds

The compounds described herein can be prepared in a variety of waysknown to one skilled in the art of organic synthesis, such as by themethods shown in the Schemes below. For example, compounds of Formula Ior II can be prepared starting from a benzamide of formula S1 as shownin Scheme 1. Accordingly, the benzamide of formula S1 is converted to aketoisocyanate or ketothioisocyanate of formula S2 by methods known inthe art. The compound of formula S2 can then be reacted with anappropriate aniline of formula S3 to give the compound of Formula I orII.

Compounds of Formula III can be prepared starting from anα-hydroxycarboxylic acid of formula S4 as shown in Scheme 2.Accordingly, the α-hydroxycarboxylic acid of formula S4 is converted toan α-chloroacyl chloride of formula S5. The compound of formula S5 canthen be reacted with an anline of formula S6 to give an α-chloroamide offormula S7. The α-chloroamide of formula S7 can then be reacted with a2-thio-pyridine N-oxide of formula S8 to give the compound of FormulaIII.

The compounds may be conveniently prepared by employing standardsynthetic methods and procedures known to those skilled in the art fromcommercially available starting materials, compounds known in theliterature, or readily prepared intermediates. Standard syntheticmethods and procedures for the preparation of organic molecules andfunctional group transformations and manipulations can be readilyobtained from the relevant scientific literature or from standardtextbooks in the field. It will be appreciated that where typical orpreferred process conditions (i.e., reaction temperatures, times, moleratios of reactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures. Those skilled in the art of organic synthesiswill recognize that the nature and order of the synthetic stepspresented may be varied for the purpose of optimizing the formation ofthe compounds.

The processes can be monitored according to any suitable method known inthe art. For example, product formation can be monitored byspectroscopic means, such as nuclear magnetic resonance spectroscopy(e.g., ¹H or ¹³C NMR) infrared spectroscopy, spectrophotometry (e.g.,UV-visible), or mass spectrometry, or by chromatography such as highperformance liquid chromatography (HPLC) or thin layer chromatography.

Preparation of compounds can involve the protection and deprotection ofvarious chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein byreference in its entirety. Adjustments to the protecting groups andformation and cleavage methods may be adjusted as necessary in light ofthe various substituents.

The reactions can be carried out in suitable solvents which can bereadily selected by one of skill in the art of organic synthesis.Suitable solvents can be substantially nonreactive with the startingmaterials (reactants), the intermediates, or products at thetemperatures at which the reactions are carried out, i.e., temperatureswhich can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, 1,1,1-trifluorotoluene, 1,2-dichloroethane,1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene,1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof andthe like.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, t-butyl methyl ether, mixtures thereof and the like.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide and ionic liquids can also be used assolvents.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by the skilledartisan. Reaction temperatures will depend on, for example, the meltingand boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures). “Elevated temperature” refers to temperatures above roomtemperature (about 22° C.).

The reactions of the processes can be carried out in air or under aninert atmosphere. Typically, reactions containing reagents or productsthat are substantially reactive with air can be carried out usingair-sensitive synthetic techniques that are well known to the skilledartisan.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonicacid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid,trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid,vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid,octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

In some embodiments, the compounds can be substantially isolated. By“substantially isolated” is meant that the compound is at leastpartially or substantially separated from the environment in which itwas formed or detected. Partial separation can include, for example, acomposition enriched in the compound or intermediate, or salt thereof.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of a compound described herein, or salt thereof.Methods for isolating compounds and their salts are routine in the art.

As used herein, the expressions, “ambient temperature” and “roomtemperature,” as used herein, are understood in the art, and refergenerally to a temperature, e.g. a reaction temperature, that is aboutthe temperature of the room in which the reaction is carried out, forexample, a temperature from about 20° C. to about 30° C.

As used herein, the term “reacting” is used as known in the art andgenerally refers to the bringing together of chemical reagents in such amanner so as to allow their interaction at the molecular level toachieve a chemical or physical transformation. In some embodiments, thereacting involves two reagents, wherein one or more equivalents ofsecond reagent are used with respect to the first reagent. The reactingsteps of the processes described herein can be conducted for a time andunder conditions suitable for preparing the identified product.

EXAMPLES

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

Example 1 PC-TP Inhibition

The compounds in Table 1 and 2 were assayed for their ability to inhibitPC-TP and StarD10, respectively, using a known assay method (see Wagleet al., 2008. Anal. Biochem. 383:85-92, which is incorporated herein byreference in its entirety). Further, certain compounds were also testedfor their ability to inhibit StarD7 (see Table 2). The activity of thecompounds at PC-TP and StarD10/StarD7, respectively, when tested at 5-10microM is shown in Tables 1 and 2.

TABLE 1 # Name Structure Activity 1 2,4-dichloro-N-(4-(N-(4,6-dimethyl-pyrimidin-2- yl)sulfamoyl)phenylcarbamothioyl) benzamide

3.2 μM 2 N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamothioyl)-4- fluorobenzamide

55% inhibition at 100 μM 3 N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamothioyl) benzamide

45% inhibition at 100 μM 4 2,4-dichloro-N-(4-(N-(4,6-dimethylpynmidin-2- yl)sulfamoyl)phenylcarbamoyl) benzamide

4.1 μM 5 2-chloro-N-(4-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl) benzamide

30 μM 6 4-chloro-N-(4-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl) benzamide

26 μM 7 2,4-dichloro-N-(4-(N-(4,6- dimethylpyridin-2-yl)sulfamoyl)phenylcarbamoyl) benzamide

5.0 μM 8 2,4-dichloro-N-(3-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl) benzamide

6.5 μM 9 2,3-dichloro-N-(4-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl) benzamide

3.2 μM 10 3,4-dichloro-N-(4-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenyl- carbamoyl)benzamide

30 μM 11 2,4-dichloro-N-((4-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenyl)(methyl) carbamoyl)benzamide

>50 μM 12 2,4-dichloro-N-(4-(N-(4,6- dimethylpyrimidin-2-yl)-N-methylsulfamoyl)phenylcarbamoyl) benzamide

2.3 μM 13 2,4-dichloro-N-(4-(N-(2,6- dimethylpyrimidin-4-yl)sulfamoyl)phenylcarbamoyl) benzamide

2.3 μM 14 2,4-dichloro-N-(4-N-(3,5- dimethylphenyl)sulfamoyl)phenylcarbamoyl)benzamide

20 μM 15 2,4-dichloro-N-(4-(N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-N- methylbenzamide

8.0 μM 16 2-(2-(3,5-dichlorophenylamino)-2-oxo-1-phenylethylthio)pyridine 1-oxide

3.6 μM 17 2-(2-(3-chloro-4-methoxyphenylamino)-2-oxo-1-phenylethylthio)pyridine 1-oxide

20 μM 18 2-(2-(3-chloro-4-methylphenylamino)-2-oxo-1-phenylethylthio)pyridine 1-oxide

100 μM 19 2-(2-oxo-1-phenyl-2-(3- (trifluoromethyl)phenylamino)ethylthio)pyridine 1-oxide

11 μM 20 2-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxo-1-phenylethylthio)pyridine 1-oxide

13 μM 21 2-(1-(2-chlorophenyl)-2-(3,5- dichlorophenylamino)-2-oxoethylthio)pyridine 1-oxide

15 μM 22 2-(2-(3,5-dichlorophenylamino)-1-(2-methoxyphenyl)-2-oxoethylthio)pyridine 1-oxide

4.1 μM 23 2-(2-(3,5-dichlorophenylamino)-1- (naphthalen-1-yl)-2-oxoethylthio)pyridine 1-oxide

12 μM 24 3-(2-(3,5-dichlorophenylamino)-2-oxo-1-phenylethylthio)isoquinoline 2-oxide

25% inhibition at 30 μM 25 2-(2-(3,5-dichlorophenylamino)-1-(4-methoxyphenyl)-2-oxoethylthio)pyridine 1-oxide

30% at 50 μM 26 2-(2-(3,5-dichlorophenylamino)-1- (naphthalen-2-yl)-2-oxoethylthio)pyridine 1-oxide

20% at 50 μM 28 2-(2-(4-chloro-2- (trifluoromethyl)phenylamino)-2-oxo-1-phenylethylthio)pyridine 1-oxide

~50 μM 29 2,4-dichloro-N-(2-(diethylamino)ethyl)-N-((4-(N-(4,6-dimethylpyrimidin-2- yl)sulfamoyl)phenyl)carbamoyl)benzamide

High fluoroescense 30 2,4-dichloro-N-((4-(N-(2-(diethylamino)ethyl)-N-(4,6- dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl) benzamide

High fluorescense 31 2-(2-(2-chloro-5-(trifluoromethyl)phenylamino)-2-oxo-1- phenylethylthio)pyridine 1-oxide

>100 μM 32 2-(2-(2-ethoxyphenylamino)-2-oxo-1- phenylethylthio)pyridine1-oxide

>100 μM 33 2-(2-(2-chlorophenylamino)-2-oxo-1- phenylethylthio)pyridine1-oxide

15 μM 34 2-(2-(2-methoxyphenylamino)-2-oxo-1- phenylethylthio)pyridine1-oxide

4 μM

TABLE 2 Compound # StarD10 IC₅₀ (μM) StarD7 IC₅₀ (μM) 4 12 63 8 14 9 3912 11 13 20 15 17 16 20 66 33 23 34 15

Example 2 Pctp^(−/−) Mice are Protected Against Diet-Induced Diabetesand Non-Alcoholic Fatty Liver Disease (NAFLD)

Considering that type 2 diabetes is characterized by hepatic insulinresistance with increased hepatic glucose production and is frequentlyaccompanied by NAFLD, Pctp^(−/−) mice were tested for resistance to dietinduced diabetes and the accumulation of hepatic triglycerides. MalePctp^(−/−) and wild type control mice were fed a high fat diet (HF; 60%kcal from fat) for 8 to 18 weeks. Percentages of body fat and leanmuscle mass were determined by magnetic resonance imaging. Fastingplasma glucose concentrations were monitored as mice became diabetic.Rates of hepatic glucose production and glucose clearance from theplasma were quantified in hyperinsulinemic euglycemic clamp studies asdescribed (Scapa, E. F., Pocai, A., Wu, M. K., Gutierrez-Juarez, R.,Glenz, L., Kanno, K., Li, H., Biddinger, S., Jelicks, L. A., Rossetti,L., and Cohen, D. E. 2008. Regulation of energy substrate utilizationand hepatic insulin sensitivity by phosphatidylcholine transferprotein/StarD2. FASEB J 22:2579-259). Liver samples were harvested formeasurements of hepatic triglyceride concentrations. Both genotypes ofmice consumed the same amounts of food, gained weight equally, andbecame obese. After 18 weeks of HF feeding, body fat and lean musclemass did not differ in Pctp^(−/−) and wild type mice. In wild type mice,fasting plasma glucose concentrations increased 1.9 fold between 8 and12 weeks of HF feeding and then leveled off. The absence of PC-TPexpression was associated with 25%, 46%, and 17% reductions in plasmaglucose at 8, 12, and 18 weeks respectively. Clamp studies performed at18 weeks of HF feeding revealed a 46% decrease in hepatic glucoseproduction rates, but no difference in rates of glucose clearance.Hepatic triglyceride concentrations (mg/g liver) were reduced inPctp^(−/−) mice at 8 weeks, but not 12 weeks.

Example 3 Pctp^(−/−) Mice are Protected Against Allergen-Induced Asthma

Mice lacking PC-TP and their wild type littermate controls weresensitized using intraperitoneal injection of ovalbumin. Mice were thenchallenged with the same allergen by an aerosolized route prior tocollecting bronchalveolar lavage fluid (Levy, B. D., De Sanctis, G. T.,Devchand, P. R., Kim, E., Ackerman, K., Schmidt, B. A., Szczeklik, W.,Drazen, J. M. and Serhan, C. N. 2002. Multi-pronged inhibition of airwayhyper-responsiveness and inflammation by lipoxin A(4). Nat. Med. 8,1018-1023). In the absence of PC-TP, concentrations of cysteinylleukotrienes decreased, with concentrations of lipoxin A₄ (LXA₄) tendingto decline as well. There was a 40% reduction in the number ofeosinophils and modest increase in macrophages. Polymorphonuclearneutrophils were not prominent in either cohort at the time ofbronchoalveolar lavage sampling. This pattern of leukocyte traffickingin the lung coupled with decrements in cysteinyl leukotrienes, which arepotent mediators of airway constriction (Leff, A. R. 2000. Role ofleukotrienes in bronchial hyperresponsiveness and cellular responses inairways. Am. J. Respir. Crit. Care Med. 161, S125-S132), suggests thatthe airway inflammation was already in the process of resolving in theanimals lacking PC-TP.

An interpretation of these data is that the reduction of eosinophils inmice lacking PC-TP was attributable to increased clearance bymacrophages. Decreased levels of both cysteinyl leukotrienes and LXA₄are consistent with the possibility that PC-TP is an important regulatorof eicosanoid formation. Of note, decreases in LXA₄ in mice lacking alsosuggest that lipoxin-independent pathways contributed to the acceleratedresolution of allergic inflammation.

Example 4 Animal Model for Asthma

Allergic airway inflammation and airway hyper-responsiveness are inducedin mice lacking PC-TP and wild type littermate control mice as described(Levy, B. D., De Sanctis, G. T., Devchand, P. R., Kim, E., Ackerman, K.,Schmidt, B. A., Szczeklik, W., Drazen, J. M. and Serhan, C. N. 2002.Multi-pronged inhibition of airway hyper-responsiveness and inflammationby lipoxin A(4). Nat. Med. 8, 1018-1023). Briefly, 5 week-old male miceare injected i.p. with 10 μg ovalbumin plus 1 mg aluminum hydroxide ondays 0 and 7. On day 14, mice are exposed to aerosolized ovalbumin (6%for 20 min) for 4 consecutive days. Following aerosol exposure on day18, mice are studied immediately (time 0), then every 2 hours for thefirst 6 hours, followed by 12 hours, 24 hours, 72 hours and 7 days. Atthe end of treatment periods, mice are subjected to bilateralbronchoalveolar lavage using 2 aliquots of 1 ml phosphate bufferedsaline containing 0.6 mM EDTA. For histological analysis, separategroups of mice are sacrificed in order to harvest lungs. Separate groupsof mice are also subjected to measurements of lung resistance using aFlexivent System. In this model, inhibitors are administered before,during and after challenge with allergen in order to determine whetherthese compounds prevent, attenuate or promote resolution of asthma.

Cells obtained by bronchoalveolar lavage are pelleted, resuspended andcounted using a hemocytometer. Cells are concentrated onto a microscopeslide and stained by Wright-Giemsa staining. The distribution ofpolymorphonuclear neutrophils, eosinophils, macrophages and lymphocytesare determined by counting ≧200 cells/sample. T lymphocytes are analyzedby fluorescence assisted cells sorting to determine the proportion ofCD4⁺, CD8⁺ and CD4⁺ T cells that express markers characteristic ofT-regulatory cells (CD25 and FoxP3).

Cell-free bronchoalveolar fluid are used to measure lipid and peptidemediators. Selected eicosanoids are measured by ELISA [Levy, 2001 #2577]and as necessary, HPLC or mass spectrometry. In order to probe forpotential differences in the lymphocytic response, concentrations ofspecific Th2 cytokines, interleukin-5 (IL-5) and IL-13 are measured.Measurements of serum ovalbumin-specific and total IgE concentrationsare correlated with the cellular composition of the inflammatoryresponse.

For the measurement of airway resistance, a thoracotomy are performedwhile the mouse is being mechanically ventilated. Thereafter,respiratory status are closely monitored while geometrically increasingdoses of methacholine chloride (a bronchoconstrictor and congener ofacetylcholine) are administered via in-line nebulizer. These experimentsdetermine whether PC-TP expression influences airwayhyper-responsiveness, as is suggested by the changes in eicosanoids andinflammatory infiltrate.

To assess the possibility that PC-TP influences eosinophil trafficking,the capacity of eosinophils to accumulate in vivo in response tochemoattractants are measured. Briefly, prostaglandin E₂ plusleukotriene B₄ in acetone are applied topically on the inside of ears ofPC-TP-deficient and wild type mice. After 13-16 h, 6 mm diameter skinpunch biopsies are taken. Samples are homogenized and analyzed foreosinophil peroxidase as a measure of tissue eosinophil concentration.

Example 5 Animal Model for Atherosclerosis

Mice with gene disruption of apoE or the low density lipoproteinreceptor (LDLr) genes develop atherosclerosis when placed on aWestern-type diet (Breslow, J. L. 1996. Mouse models of atherosclerosis.Science 272, 685-688). Mice lacking both apoE and PC-TP generallydevelop less atherosclerosis than apoE mice alone (Wang, W. J., Baez, J.M., Maurer, R., Dansky, H. M., and Cohen, D. E. 2006. Homozygousdisruption of Pctp modulates atherosclerosis in apolipoprotein Edeficient mice. J. Lipid Res. 47:2400-2407). Mice lacking apoE or LDLrare fed a western diet. These mice are treated with PC-TP inhibitorsduring the period when they develop atherosclerosis to assess theircapacity to prevent atherosclerosis. The dosing, frequency and route ofadministration of compounds depends upon pharmacokinetics of thecompounds, but ideal compounds will be given no more frequently thanonce per day. The compounds are also tested for the capacities to treatatherosclerosis by waiting until atherosclerosis is established in thesemodels before administering them. Mice lacking both PC-TP and apoE orLDLr (which can be readily prepared by breeding) serve as positivecontrols for the capability of the inhibitors to preventatherosclerosis. However, they cannot serve as positive controls foratherosclerosis treatment because the gene is chronically absent inthese mice. Nevertheless, negative controls administered vehicle alonemay provide the requisite information about whether the PC-TP inhibitorsare effective at atherosclerosis treatment. The effectiveness ofinhibitors will be assessed by quantification of atherosclerosis andinfluence on plasma lipids as we have previously described (Wang, W. J.,Baez, J. M., Maurer, R., Dansky, H. M., and Cohen, D. E. 2006.Homozygous disruption of Pctp modulates atherosclerosis inapolipoprotein E deficient mice. J. Lipid Res. 47:2400-2407).

Example 6 Animal Model for Type 2 Diabetes and Obesity

When fed a high fat diet, FVB/NJ mice develop both diabetes and obesity(Martin, T. L., Alquier, T., Asakura, K., Furukawa, N., Preitner, F. andKahn, B. B. 2006. Diet-induced obesity alters AMP kinase activity inhypothalamus and skeletal muscle. J. Biol. Chem. 281, 18933-18941).Because mice lacking PC-TP were crossed to this genetic background (Wu,M. K., Hyogo, H., Yadav, S., Novikoff, P. M. and Cohen, D. E. 2005.Impaired response of biliary lipid secretion to a lithogenic diet inphosphatidylcholine transfer protein-deficient mice. J. Lipid Res. 46,422-431), this model has been used to demonstrate that the absence ofPC-TP expression protects against diabetes and obesity in the setting of8 weeks of high fat feeding (see above). These mice are used to testinhibitor compounds for the prevention and treatment of diabetes andobesity by initiating treatment at the time that high fat feedingcommences or by administering them once diabetes and obesity areestablished. The effectiveness of compounds in preventing and treatingobesity is assessed by measuring weights, food consumption and body fatdistribution as we have described (Scapa, E. F., Pocai, A., Wu, M. K.,Gutierrez-Juarez, R., Glenz, L., Kanno, K., Li, H., Biddinger, S.,Jelicks, L. A., Rossetti, L., and Cohen, D. E. 2008. Regulation ofenergy substrate utilization and hepatic insulin sensitivity byphosphatidylcholine transfer protein/StarD2. FASEB J. 22:2579-259). Theinfluence of inhibitors on diabetes will be assessed in detailed studiesof glucose metabolism as we have described (Scapa, E. F., Pocai, A., Wu,M. K., Gutierrez-Juarez, R., Glenz, L., Kanno, K., Li, H., Biddinger,S., Jelicks, L. A., Rossetti, L., and Cohen, D. E. 2008. Regulation ofenergy substrate utilization and hepatic insulin sensitivity byphosphatidylcholine transfer protein/StarD2. FASEB J 22:2579-259).

Example 7 PC-TP Inhibitors Enhance the Insulin Signaling Pathway inHuman Hepatocytes, Even in the Absence of Insulin

Cultured primary human hepatocytes (commercially obtained) were serumstarved overnight followed by 60 minute exposure to A) Compound 4 or B)Compound 16 at the indicated concentrations. Inhibitors were dissolvedin DMSO. Negative controls included Control (no additions) and DMSOalone. The positive control included DMSO plus insulin (50 nM) for 30minutes. Cells were harvested and lysates were subjected to immunoblotanalyses using antibodies, as indicated. Both inhibitors activatedinsulin signaling at doses of 0.05 and 0.10 μM. Results are shown inFIG. 1.

Example 8 Surface Plasmon Resonance of Compound 8 Binding to PC-TP

Compound 8 was injected into a Biacore 3000 surface plasmon resonanceinstrument with purified recombinant His-tag PC-TP immobilized to acarboxymethyl dextran 5 (CM %) chip for 150 s and allowed to dissociate.Each sensogram was overlaid and zeroed on the y-axis to the averagebaseline before injection. The start injection time for each sample wasset to zero on the x-axis (see FIG. 2). The K_(D) value was 5.0 μM.

Example 9 Displacement Assay of PC-TP Using a Pyrene-Labeled PC

Competition between the small molecule inhibitors and fluorescentpyrene-labeled phosphatidylcholine (PyrPC) for binding to PC-TP wasmeasured using Pyr-PC fluorescent vesicles quenched withtetracyanoquinodimethane (TCNQ) (Lemmetyinen H. et al. 1989). Uponmixing of quenched Pyr-PC vesicles with purified recombinant PC-TP, therise in Pyr-PC fluorescence reflects binding of fluorescently labeledphosphatidylcholine molecules to the active site of PC-TP. If the smallmolecule inhibitors enter the active site and prevent binding ofphosphatidylcholine to PC-TP by competing the Pyr-PC, this should reducethe observed increase in Pyr-PC fluorescence.

The fluorescence of PyrPC monomer was measured at 392 nm on SpectraMaxM5 plate-reader with excitation was set at 345 nm. Pyrene-labeled PCvesicles contained PyrPC, egg PC, and TCNQ in a molar ratio of 40:20:60.For PC and PyrPC competition assays, we used unlabeled PC vesiclescomposed of egg PC and TCNQ in a molar ratio of 55:45 or PC vesicles ofvaried lipid concentrations and PyrPC vesicles quenched with TCNQ(55:45). In order to determine the affinity of PC-TP for Compound 4relative to PyrPC, PyrPC lipid binding was measured using varyingconcentrations of inhibitor 5, 20, 50, and 75 μM and a fixed amount ofPyrPC (36 μM). To determine the affinity of eggPC compared to PyrPC, wevaried the concentration of egg PC in the assay as follows: 5, 11, 22,27, 33, and 44 μM, and a fixed amount of PyrPC (44 μM). The wells whereunlabeled PC concentration was less than 44 μM were supplemented withadditional amounts of TCNQ to keep the concentration of the quencherequal in all the wells. In another assay, multiple egg PC:TCNQ vesiclesof varied lipid concentration were prepared separately as follows,10:20, 40:20, 60:20, 80:20 molar ratios of PC:TCNQ and bindingcompetition for PC-TP was tested against PyrPC:TCNQ vesicles (40:40).PC-TP concentration was kept constant at 300 nM. In the displacementassay, the increase in pyrene monomer fluorescence (ΔF) is proportionalto the amount of [Pyr], pyrene-labeled PC bound to PC-TP. The maximalfluorescence increase (ΔF_(max)) at pyrene monomer emission peak(˜380-394 nm) is observed in the absence of inhibitor ([inh]=0) orunlabeled lipid ([PC]=0). The fluorescence reading of wells with PyrPCvesicles alone and Pyr-PC vesicles with inhibitor (highest backgroundfluorescence) were used as control and subtracted as background.Increasing Compound 4 concentration resulted in diminishing fluorescenceof pyrene monomer suggesting that the inhibitor entered and bound to theactive site and thus, prevented Pyr-PC from binding to PC-TP. Incontrast, no change in fluorescence was observed upon addition of aninactive compound, which was also found to have no inhibitory effect onPC transfer activity.

As described in Van Paridon et al. 1987, by plotting ΔF as a function ofΔF·[inh]/[Pyr] (▪) or ΔF·[PC]/[Pyr] (●), a straight line is obtainedwith a slope of −1/K_(rel), where K_(rel) is relative affinity constant(FIG. 3). The K_(rel) value is estimated by least-squares fitting of thedata. From the plot K_(rel) (Compound 4/PyrPC) was estimated as1.1+/−0.36, whereas K_(rel) (PC/PyrPC)=5.0+/−0.78 (Note: the aboveK_(rel) values are averaged K_(rel) values obtained from multipleexperiments). Therefore, K_(rel) (Compound 4/PC) can be calculated asK_(rel) (Compound 4/PyrPC)/K_(rel) (PC/PyrPC)=0.22. These findingssuggest that the inhibitor is capable of displacing PC from the activesite of PC-TP.

References: Lemmetyinen H., Yliperttula M., Mikkola J., Kinnunen P.Quenching of fluorescence of pyrene-substituted lecithin bytetracyanoquinodimethane in liposomes. Biophys. J., 55 (1989) 885-895;Van Paridon P. A., Gadella T. W. J., Somerharju P. J., Wirtz K. W. A. Onthe relationship between the dual specificity of the bovine brainphosphatidylinositol transfer protein and membrane phosphatidylinositollevels. Biochim. Biophys. Acta, 903 (1987) 68-77.

Example 10 Preparation of Compounds of Formula I

Compounds of Formula I can be formed as shown below in Scheme A1 orScheme A2.

To a solution of 1 (1 mmol) in dichloroethane (DCE; 15 mL) was addedoxalyl chloride (500 μL). The mixture was then heated at 80° C. for 18 hbefore being concentrated to dry. Toluene (10 mL×2) was added to theresidue and concentrated until a white solid formed. This solid, 2, wasused in next step without further purification.

A mixture of 2 and 3 (1 mmol) in CH₃CN was heated at 80° C. for 5 h. Theformed solid was collected by filtration and purified by prep-HPLC togive 4 as white solid.

The following are ¹H NMR spectra of representative examples preparedutilizing the procedure described in Scheme A1:

(Compound 1): ¹H NMR (d₆-DMSO, 500 MHz) δ 12.38 (s, 1H), 12.12 (s, 1H),8.01 (d, 2H, J=9.0 Hz), 7.90 (d, 2H, J=9.0 Hz), 7.77 (d, 1H, J=2.0 Hz),7.67 (d, 1H, J=7.0 Hz), 7.57 (dd, 1H, J=2.0, 7.0 Hz), 6.78 (s, 1H), 2.26(s, 6H).

(Compound 5): ¹H NMR (CDCl₃, 500 MHz) δ 10.85 (s, 1H), 8.70 (s, 1H),8.01 (d, 2H, J=9.0 Hz), 7.65-7.25 (m, 7H), 6.55 (s, 1H), 2.28 (s, 6H).

(Compound 6): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.20 (s, 1H), 11.00 (s, 1H),8.1-7.90 (m, 4H), 7.78-7.62 (m, 4H), 6.75 (s, 1H), 2.28 (s, 6H).

(Compound 7): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.3 (s, 1H), 10.5 (s, 1H),8.40 (s, 1H), 7.80 (2, 7H), 6.80 (s, 1H), 6.40 (s, 1H), 2.18 (s, 3H),2.10 (s, 3H).

(Compound 8): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.2 (s, 1H), 10.38 (s, 1H),8.4 (s, 1H), 7.80 (d, 2H, J=2.0 Hz), 7.73-7.50 (m, 5H), 6.78 (s, 1H),2.28 (s, 6H).

(Compound 4): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.38 (s, 1H), 10.55 (s, 1H),7.98 (d, 2H, J=2.0 Hz), 7.80-7.5 (m, 6H), 6.78 (s, 1H), 2.28 (s, 6H).

(Compound 11): ¹H NMR (d₆-DMSO, 500 MHz) δ 10.6 (s, 1H), 7.95 (d, 2H,J=2.0 Hz), 7.60-7.30 (m, 5H), 6.68 (s, 1H), 3.26 (s, 3H), 2.30 (s, 6H).

(Compound 9): ¹H NMR (d₆-DMSO, 500 MHz) δ 10.48 (s, 1H), 7.95 (d, 2H,J=2.0 Hz), 7.75-7.40 (m, 5H), 6.75 (s, 1H), 2.25 (s, 6H).

(Compound 12): ¹H NMR (d₆-DMSO, 500 MHz) δ 8.00 (d, 2H, J=2.0 Hz),7.75-7.55 (m, 5H), 6.82 (s, 1H), 3.55 (s, 3H), 2.28 (s, 6H).

(Compound 10): ¹H NMR (d₆-DMSO, 500 MHz) δ 8.2 (s, 1H), 8.0-7.70 (m,7H), 6.75 (s, 1H), 2.22 (s, 6H).

(Compound 13): ¹H NMR (d₆-DMSO, 500 MHz) δ 10.5 (s, 1H), 10.0 (s, 1H),7.75-7.45 (m, 7H), 6.75 (s, 2H), 6.65 (s, 1H), 2.15 (s, 6H).

(Compound 14): ¹H NMR (d₆-DMSO, 500 MHz) δ 10.5 (s, 1H), 7.9-7.55 (m,8H), 2.35 (s, 3H), 2.25 (s, 3H).

To a suspension of A (278 mg, 1 mmol) in toluene (5 mL) was addedphosgene (20% in toluene, 2 mL). The mixture was stirred 30 min at roomtemperature and then was heated at 80° C. for 2 h before beingconcentrated to dryness. Toluene (10 mL×2) was added to the residue andconcentrated. This solid, B, was used in next step without furtherpurification.

To a solution of C (102 mg, 0.5 mmol) in THF (5 mL) was added NaH (30mg, 0.75 mmol). The mixture was stirred at room temperature for 30 min,then B (152 mg, 0.5 mmol) was added. The resulted mixture was heated at80° C. for 5 h. The formed solid was collected by filtration andpurified by prep-HPLC to give Compound 15 as white solid (120 mg, 47%).

(Compound 15): ¹H NMR (d₆-DMSO, 400 MHz) δ 10.6 (s, 1H), 7.84 (d, 2H,J=8.4 Hz), 7.54-7.50 (m, 6H), 3.18 (s, 3H), 2.13 (s, 6H).

Example 9 Preparation of Compounds of Formula III

Compounds of Formula III can be formed as shown below in Scheme B.

To a solution of 5 (2 mmol) in MeOH (15 mL) was added NaOH (6N, 333 μL).The reaction was stirred at room temperature for 30 min. The solution of6 was used directed for the next step.

To a solution of 6 was added 7 (2 mmol) and the resulting solution wasstirred at 70° C. for 30 min. The resulted mixture was neutralized withKHSO₄ (350 mg, 3 mmol) in H₂O (20 mL) and then concentrated to partiallyremove the solvents. The solid residue was filtered to give 8 as a whitecrystalline solid.

A mixture of 8 (1 mmol), 9 (1.2 mmol), HATU (460 mg, 1.2 mmol), andiPr2NEt (350 μL, 2 mmol) in DMF (10 mL) was stirred at room temperaturefor 18 h. After diluting with water the reaction mixture was extractedwith ethyl acetate. The organic later was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified byprep-HPLC to give 10 as a white solid.

The following are ¹H NMR spectra of representative examples preparedutilizing the procedure described in Scheme B:

(Compound 16): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.38 (s, 1H), 8.33 (d, 1H,J=6.0 Hz), 7.69 (d, 2H, J=2.0 Hz), 7.65 (d, 2H, J=2.0 Hz), 7.67 (d, 1H,J=7.5 Hz), 7.43-7.40 (m, 2H), 7.37-7.34 (m, 3H), 7.32-7.31 (m, 1H),7.24-7.22 (m, 1H), 5.66 (s, 1H).

(Compound 17): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.2 (s, 1H), 8.36 (d, 1H),7.70-7.63 (m, 4H), 7.47-7.22 (m, 7H), 5.58 (s, 1H).

(Compound 20): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.30 (s, 1H), 8.33 (d, 1H,J=7.0 Hz), 8.25 (s, 1H), 7.80 (s, 1H), 7.63-7.61 (m, 2H), 7.42-7.22 (m,6H), 5.53 (s, 1H).

(Compound 24): ¹H NMR (CDCl₃, 500 MHz) δ 10.7 (s, 1H), 8.85 (s, 1H),7.75-7.25 (m, 12H), 7.00 (s, 1H), 5.35 (s, 1H).

(Compound 21): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.0 (s, 1H), 8.38 (d, 1H,J=7.0 Hz), 7.64-7.22 (m, 10H), 5.70 (s, 1H).

(Compound 23): ¹H NMR (d₆-DMSO, 500 MHz) δ 10.89 (s, 1H), 8.55 (d, 1H,J=7.0 Hz), 8.20-8.18 (m, 1H), 7.98-7.40 (m, 12H), 6.45 (s, 1H).

(Compound 26): ¹H NMR (d₆-DMSO, 500 MHz) δ 11.0 (s, 1H), 8.30 (d, 1H,J=7.0 Hz), 8.10 (s, 1H), 7.98-7.20 (m, 12H), 5.65 (s, 1H).

(Compound 22): ¹H NMR (d₆-DMSO, 500 MHz) δ 10.88 (s, 1H), 8.38 (d, 1H,J=7.0 Hz), 7.72 (s, 2H), 7.55-7.00 (m, 8H), 5.70 (s, 1H), 3.92 (s, 3H).

Compounds 33 and 34 were synthesized by a method analogous to that forCompounds 21 and 22.

Compounds 2, 18, 19, and 28 were obtained from Ryan Scientific (Mt.Pleasant, S.C.). Compound 3 was obtained from ChemBridge (San Diego,Calif.). Compounds 31 and 32 were purchased from Enamine

Compound 29.2,4-dichloro-N-(2-(diethylamino)ethyl)-N-((4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl)benzamide

The compound was prepared as in the scheme below. Reagents andconditions: 2-chloro-N,N-diethylethylamine hydrochloride,tetrabutyl-ammonium bromide (TBAB), NaOH, Toluene, H₂O, 100° C., 14hours, 33%.

A mixture of corresponding benzenesulfonamide (1) (100 mg, 0.20 mmol),2-chloro-N,N-diethylamine hydrochloride (42 mg, 0.24 mmol), TBAB (65 mg,0.20 mmol), sodium hydroxide (24 mg, 0.61 mmol), toluene 2 mL, and water2 mL was stirred at reflux for 14 hours. After cooling, the mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was chromatographed on a silica gelcolumn eluting with 5% methanol in dichloromethane to give 2 (40 mg,33%). ¹H NMR (500 MHz, CDCl₃) δ 8.20-8.12 (m, 3H), 7.78-7.70 (m, 3H),7.48 (d, J=2.0 Hz, 1H), 7.38 (dd, J=2.0, 8.5 Hz, 1H), 6.57 (s, 1H),4.32-4.22 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.70 (q, J=7.0 Hz, 4H), 2.30(s, 6H), 1.13 (t, J=7.0 Hz, 6H).

Compound 30.2,4-dichloro-N-((4-(N-(2-(diethylamino)ethyl)-N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl)benzamide

The compound was prepared as in the scheme below.

Reagents and conditions: (a) 2-chloro-N,N-diethylethylaminehydrochloride, tetrabutyl-ammonium bromide (TBAB), NaOH, Toluene, H₂O,100° C., 12 hours; (b) iron, HCl, ethanol, H₂O, 100° C., 2 h; (c) oxalylchloride, ClCH₂CH₂Cl, 80° C., 18 hours; (d) CH₃CN, 80° C., 5 hours.

(a) 2-chloro-N,N-diethylethylamine hydrochloride, tetrabutyl-ammoniumbromide (TBAB), NaOH, Toluene, H₂O, 100° C., 14 hours, 33%. Concentratedmixture was used in next step without further purification.

(b) A mixture of compound obtained above (0.162 mmol), iron (360 mg,0.63 mmol), NH₄Cl (182 mg, 0.34 mmol), ethanol (20 mL), and water (10mL) was heated at 100° C. for 2 hours. After cooling, the mixture wasfiltered through celite, extracted with ethyl acetate, washed withbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas used directly without further purification.

(c) To a solution of 2,4-dichlorobenzamide (380 mg, 2 mmol) in1,2-dichloroethane was added oxalyl chloride (1.0 mL, 11.4 mmol). Themixture was then heated at 80° C. for 18 hours before being concentratedto dryness. Toluene (20 mL×2) was added to the residue and concentrateduntil 4, a white solid formed. This solid was used in next step withoutfurther purification.

(d) A solution of 2 (1.0 mmol) and 4 (0.2 mmol) in 8 mL of acetonitrilewas heated at 95° C. for 48 hours. After cooling, the mixture wasconcentrated. The residue was chromatographed on a silica gel columneluting with 5% Methanol in dichloromethane to give 5 (30 mg, 25% in 4steps).

¹H NMR (500 MHz, CDCl₃) δ 8.20-8.05 (m, 2H), 7.85-7.30 (m, 5H), 6.63 (d,J=2.0 Hz, 1H), 4.56 (t, J=7.0 Hz, 2H), 3.45 (brs, 2H), 3.18 (brs, 4H),2.33 (s, 6H), 1.48 (brs, 6H).

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

APPENDIX 1

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein: X is N, Y is N,and Z is CH; X is N, Y is CH, and Z is N; R′, R″, and R′″ are eachindependently selected from H and C₁₋₃ alkyl; R¹, R², R³, R⁴, and R⁵ areeach independently selected from H, halogen, cyano, hydroxyl, carboxyl,carbamyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl,and C₁₋₆ alkylsulfonyl; R⁶ and R⁷ are each C₁₋₆ alkyl; n is 0; W is O;each R¹¹ is independently selected from halogen, cyano, nitro, hydroxyl,carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylcarbonylamino, di-C₁₋₆alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl provided that: when the compound has Formula I, W is O, Xis N, Y is N, and Z is CR¹⁰, then the following provisos apply: (a) whenR⁶ and R⁷ are each methyl, R¹⁰ is H, and R¹, R², R⁴, and R⁵ are H, thenR³ is not methoxy or chloro; and (b) when R⁶ and R⁷ are each methyl andR¹⁰ is H, then at least one of R¹, R², R³, R⁴, and R⁵ is other than H.2. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹, R², R³, R⁴, and R⁵ are each independentlyselected from H and halogen.
 3. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶ and R⁷ are eachmethyl.
 4. The compound according to claim 1, wherein the compound is acompound of Formula Ia:

or a pharmaceutically acceptable salt thereof.
 5. The compound accordingto claim 1, which is selected from:2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;2-chloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;2,3-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;3,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;2,4-dichloro-N-((4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)(methyl)carbamoyl)benzamide;2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)-N-methylsulfamoyl)phenylcarbamoyl)benzamide;2,4-dichloro-N-(4-(N-(2,6-dimethylpyrimidin-4-yl)sulfamoyl)phenylcarbamoyl)benzamide;and2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)-N-methylbenzamide;or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 1, which is selected from:2,4-dichloro-N-(2-(diethylamino)ethyl)-N-((4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl)benzamide;and2,4-dichloro-N-((4-(N-(2-(diethylamino)ethyl)-N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenyl)carbamoyl)benzamide;or a pharmaceutically acceptable salt thereof.
 7. A compound accordingto claim 1, which is2,4-dichloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 9. A method of treating a disorder selectedfrom obesity, type 2 diabetes, non-alcoholic fatty liver disease,asthma, hyperlipidemia, coronary artery disease, arthritis, gallstones,and atherosclerosis in a patient in need thereof, comprisingadministering to said patient a compound of claim 1, or apharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound of claim 7, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 11.The pharmaceutical composition according to claim 8, wherein thecompound is selected from:4-chloro-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;and2,4-dichloro-N-(3-(N-(4,6-dimethylpyrimidin-2-yl)sulfamoyl)phenylcarbamoyl)benzamide;or a pharmaceutically acceptable salt thereof.
 12. A method of treatingobesity, type 2 diabetes, non-alcoholic fatty liver disease, asthma,hyperlipidemia, coronary artery disease, arthritis, gallstones, andatherosclerosis in a patient in need thereof, comprising administeringto said patient a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is N, Y is N,and Z is CH; or X is N, Y is CH, and Z is N; or R′, R″, and R′″ are eachindependently selected from H and C₁₋₃ alkyl; R¹, R², R³, R⁴, and R⁵ areeach independently selected from H, halogen, cyano, nitro, hydroxyl,carboxyl, carbamyl, amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino,di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl,and C₁₋₆ alkylsulfonyl; R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independentlyselected from H, halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl,amino, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylamino, di-C₁₋₆-alkylamino, C₁₋₆alkylcarbamyl, di-C₁₋₆ alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylthio, and C₁₋₆ alkylsulfinyl, and C₁₋₆alkylsulfonyl; n is 0; and W is O; each R¹¹ is independently selectedfrom halogen, cyano, nitro, hydroxyl, carboxyl, carbamyl, amino, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, alkylamino, di-C₁₋₆-alkylamino, C₁₋₆ alkylcarbamyl, di-C₁₋₆alkylcarbamyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylcarbonylamino, di-C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, and C₁₋₆ alkylsulfonyl.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R′, R″, and R′″ areeach independently selected from H and methyl; and R¹, R², R³, R⁴, andR⁵ are each independently selected from H and halogen.
 14. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein: R′,R″, and R′″ are each independently selected from H and methyl; and R¹,R², R³, R⁴, and R⁵ are each independently selected from H and chloro.15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having Formula Ib:

or a pharmaceutically acceptable salt thereof.
 16. The method of claim9, wherein the compound is the compound of claim 7, or apharmaceutically acceptable salt thereof.
 17. The method of claim 9,wherein the disorder is obesity.
 18. The method of claim 9, wherein thedisorder is type 2 diabetes.
 19. The method of claim 9, wherein thedisorder is atherosclerosis.
 20. The method of claim 9, wherein thedisorder is non-alcoholic fatty liver disease.
 21. The method of claim9, wherein the disorder is asthma.